The protein tyrosine phosphatases are enzymes that specifically dephosphorylate phosphotyrosine in proteins. As such, they could attenuate the signal generated by the insulin receptor and thus contribute to insulin resistance. The objectives of these studies are 1) to determine if subjects with insulin resistance have abnormally high protein tyrosine phosphatase activity in skeletal muscle, 2) to determine if insulin regulates one or more protein tyrosine phosphatase activities in skeletal muscle, and 3) to determine if the effect of insulin on PTPase activity in skeletal muscle is altered in insulin resistance. The influence of insulin on PTPase activities in human skeletal muscle has been examined in 10 insulin-sensitive and 7 insulin-resistant Pima Indians. Basal PTPase activity in the soluble fraction was the same in sensitive and resistant subjects. In the particulate fraction, however, basal PTPase activity was 30% higher in resistant subjects than in sensitive subjects. Soluble PTPase activity was rapidly suppressed by 25-30% in response to insulin infusion in insulin-sensitive subjects. The effect of insulin was maximal by 15 minutes of insulin infusion and persisted throughout 45 minutes of the insulin infusion. In contrast, insulin had very little effect on soluble PTPase activity in resistant subjects. The difference between sensitive and resistant subjects was particularly apparent at early time points, such as 15 minutes, where the effect in sensitive subjects was maximal and there was virtually no effect of insulin on soluble PTPase activity in resistant subjects.